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What is Childhood Ataxia with diffuse Central Nervous System Hypomyelination (CACH/VWM)?

Childhood Ataxia with diffuse Central Nervous System Hypomyelination Disease (CACH/VWM) is progressive inherited disorder that mainly affects the brain and spinal cord (central nervous system). This disorder causes deterioration of the central nervous system’s white matter, which is known as Myelin. Myelin is the fatty substance that insulates and protects the sending arm of the Neuron (Axon). In most cases, people with Childhood Ataxia with diffuse Central Nervous System Hypomyelination show no signs or symptoms of the disorder at birth. Affected children may have slightly delayed development of motor skills such as crawling or walking. During early childhood, most affected individuals begin to develop problems with their motor skills, including abnormal muscle stiffness (spasticity) and difficulty with coordinating movements (ataxia). There may also be some deterioration of mental functioning, but this is not usually as pronounced as the motor function. Some affected females may have abnormal development of the ovaries (ovarian dysgenesis). Specific changes in the brain as seen using magnetic resonance imaging (MRI) are characteristic of Childhood Ataxia with diffuse Central Nervous System Hypomyelination, and may be visible before the onset of symptoms.

While childhood onset is the most common form of Childhood Ataxia with diffuse Central Nervous System Hypomyelination, some severe forms are apparent at birth. A severe, early-onset form seen among the Cree and Chippewayan populations of Quebec and Manitoba is called Cree Leukodystrophy. Milder forms may not become evident until adolescence or adulthood, when behavioral or psychiatric problems may be the first signs of the disease. Some females with milder forms of Childhood Ataxia with diffuse Central Nervous System Hypomyelination who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called Ovarioleukodystrophy.

It is inherited in an autosomal recessive manner, meaning that it is a genetic disease and both parents must have the mutation. Symptoms generally appear in young children who may have been appearing to develop fairly normally. However, it has been shown recently that it can begin at or shortly after birth, as well, or even in adulthood. A striking feature of the disease is that the symptoms get worse slowly for the most part, but there are episodes of rapid deterioration that follow an infection or head trauma. The patient may have a partial recovery following these episodes, or the episode may lead to coma and death.

What causes CACH/VWM?

CACH/VWM is caused by mutations in one of the five genes that are collectively called eIF2B, or eukaryotic initiation factor 2B. This gene is necessary to properly make proteins in the body; it is so important that no one can be born with a complete absence of this gene. CACH/VWM is caused by changes in these genes that reduce the function of eIF2B. This reduction in function becomes a particular problem during episodes of fever, infection, or head traumas, and deterioration accelerates following such episodes.

The EIF2B1, EIF2B2, EIF2B3, EIF2B4 and EIF2B5 genes provide instructions for making the five parts (subunits) of a protein called eIF2B. The eIF2B protein helps regulate overall protein production (synthesis) in the cell by interacting with another protein, eIF2. The eIF2 protein is called an initiation factor because it is involved in starting (initiating) protein synthesis. Proper regulation of protein synthesis is vital for ensuring that the correct levels of protein are available for the cell to cope with changing conditions. For example, cells must synthesize protein much faster if they are multiplying than if they are in a resting state.

Mutations have been identified in all five of the genes from which the eIF2B protein is produced, although most of these mutations (about 65 percent) occur in the EIF2B5 gene. These mutations cause partial loss of eIF2B function in various ways. For example, they may impair the ability of one of the protein subunits to form a complex with the others, or make it more difficult for the protein to attach to the initiation factor.

Partial loss of eIF2B function makes it more difficult for the body’s cells to regulate protein synthesis and deal with changing conditions and stress. Researchers believe that cells in the white matter may be particularly affected by an abnormal response to stress, resulting in the signs and symptoms of Leukodystrophy with Childhood Ataxia with diffuse Central Nervous System Hypomyelination.

Forms of CACH/VWM

Antenatal form

The antenatal onset form presents in the third trimester of pregnancy with oligohydramnios and decreased foetal movement. Clinical features that may be noted soon after birth include feeding difficulties, vomiting, hypotonia, mild contractures, and cataract (sometimes oil droplet cataract) and microcephaly. Apathy, intractable seizures, and finally apneic spells and coma follow. Other organ involvement can include hepatosplenomegaly, renal hypoplasia, pancreatitis, and ovarian dysgenesis.

The clinical course is rapidly and relentlessly downhill; the adverse effect of stress factors is less clear. So far, all infants with neonatal presentation have died within the first year of life.

Infantile form

A rapidly fatal severe form of CACH/VWM is characterized by onset in the first year of life and death a few months later.

Another infantile-onset phenotype was described as “Cree Leukoencephalopathy” because of its occurrence in the native North American Cree and Chippewayan indigenous population Infants typically have hypotonia followed by sudden onset of seizures (age 3-6 months), spasticity, rapid breathing, vomiting (often with fever), developmental regression, blindness, lethargy, and cessation of head growth, with death by age two years.

Early childhood onset form

Initially most children develop normally; some have mild motor or speech delay. New onset ataxia is the most common initial symptom between ages one and five years. Some children develop dysmetric tremor or become comatose spontaneously or acutely following mild head trauma or febrile illness.

Subsequently, generally progressive deterioration results in increasing difficulty in walking, tremor, spasticity with hyperreflexia, dysarthria, and seizures. Once a child becomes nonambulatory, the clinical course may remain stable for several years. Swallowing difficulties and optic atrophy develop late in the disease.

Head circumference is usually normal; however, severe progressive megalencephaly occurring after age two years has been reported microcephaly has also been observed. The peripheral nervous system is usually normal, although predominantly sensory nerve involvement has been reported in recent. Intellectual abilities are relatively preserved.

The time course of disease progression varies from individual to individual even within the same family, ranging from rapid progression with death occurring one to five years after onset to very slow progression with death occurring many years after onset.

Late childhood/juvenile onset form

Children develop symptoms between ages five and 15 years. They often have a more slowly progressive spastic diplegia, relative sparing of cognitive ability, and likely long-term survival with long periods of stability and even improvement of motor function. However, rapid progression and death after a few months have also been described.

Adult onset form

Behavioral problems associated with cognitive decline are frequently reported before neurologic symptoms appear acute, transient neurologic symptoms (optic neuritis, hemiparesis) or severe headache, as well as primary or secondary amenorrhea in females, can be the presenting symptoms.

Asymptomatic and symptomatic adults with two mutations in one of the genes and a typically affected sibling have also been described

How do we diagnose CACH/VWM?

VWM is diagnosed on the basis of the clinical symptoms in combination with the results of an MRI. In addition, because the specific genetic defect that causes VWM is known, DNA techniques can also be used to confirm VWM.

What are the symptoms of CACH/VWM?

Generally, a child with VWM will appear relatively normal at birth, though he/she may have slightly delayed psychomotor development. Symptoms may appear beginning in late infancy or early childhood, and can vary widely from case to case of VWM. We have listed some possible symptoms below as well as definitions as necessary:

Neurological deterioration

Febrile episodes: episodes of fever. In VWM, this is associated with worsening of symptoms, drowsiness or coma.

Spasticity: This means that the child tends to suffer spasms, or involuntary contractions of muscles. Muscles are abnormally stiff and movement is restricted.

Death: will generally occur after a variable period ranging from a few years to a few decades. Normally, death results from an episode of fever and/or coma.

Ovary dysgenesis: defective development of the ovaries.

Cerebellar ataxia: loss of muscle coordination as a result of abnormal functioning of the cerebellum (a part of the brain).

Optic atrophy (variably present): an abnormality of the eyes.

Seizures

Mental impairment may be present, though generally less severe than the motor dysfunction

The motor difficulties of VWM are progressive, but the progression is often stepwise in association with fever or injuries. Prolonged periods of stability or even transient mild improvements lasting years are common. Most patients develop seizures (epilepsy) late in the illness that are easy to control. Life expectancy is reduced, though patients can live into their second or third decades.

Treatments for CACH/VWM:

There is no cure for VWM; treatment is supportive and symptomatic

Incidence:

The prevalence of CACH/VWM is unknown.

Inheritance:

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How is scientific research on CACH/VWM progressing towards improved treatment or diagnosis?

The identification of the genetic basis of CACH/VWM was a great step forward. It allows scientists to develop genetic methods of diagnosing CACH/VWM, which can lead to the possibility of genetic testing for the disease. If you know that the disease runs in your family, you can talk to a genetic counsellor about the option of prenatal testing, as well as testing of family members so that they can find out if they are carriers of the disease.

Other Clinical Names for Childhood Ataxia with diffuse Central Nervous System Hypomyelination Disease